ABSTRACT
Peritoneum is the most common site for ovarian cancer metastasis. Here we investigate how cancer epigenetics regulates reciprocal tumor-stromal interactions in peritoneal metastasis of ovarian cancer. Firstly, we find that omental stromal fibroblasts enhance colony formation of metastatic ovarian cancer cells, and de novo expression of transforming growth factor-alpha (TGF-α) is induced in stromal fibroblasts co-cultured with ovarian cancer cells. We also observed an over-expression of tumor necrosis factor-alpha (TNF-α) in ovarian cancer cells, which is regulated by promoter DNA hypomethylation as well as chromatin remodeling. Interestingly, this ovarian cancer-derived TNF-α induces TGF-α transcription in stromal fibroblasts through nuclear factor-κB (NF-κB). We further show that TGF-α secreted by stromal fibroblasts in turn promotes peritoneal metastasis of ovarian cancer through epidermal growth factor receptor (EGFR) signaling. Finally, we identify a TNFα-TGFα-EGFR interacting loop between tumor and stromal compartments of human omental metastases. Our results therefore demonstrate cancer epigenetics induces a loop of cancer-stroma-cancer interaction in omental microenvironment that promotes peritoneal metastasis of ovarian cancer cells via TNFα-TGFα-EGFR.
Subject(s)
ErbB Receptors/metabolism , Neoplasm Proteins/metabolism , Ovarian Neoplasms/metabolism , Peritoneal Neoplasms/metabolism , Transforming Growth Factor alpha/metabolism , Tumor Microenvironment , Tumor Necrosis Factor-alpha/metabolism , Adult , Aged , Animals , Cell Communication , Cell Line, Tumor , Female , Fibroblasts/metabolism , Fibroblasts/pathology , Humans , Mice , Mice, Nude , Middle Aged , Neoplasm Metastasis , Neoplasm Transplantation , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/pathology , Peritoneal Neoplasms/secondary , Stromal Cells/metabolism , Stromal Cells/pathologySubject(s)
Antibodies, Antineutrophil Cytoplasmic/immunology , Glomerulonephritis/pathology , Leukemia, Lymphocytic, Chronic, B-Cell/pathology , Aged , B-Lymphocytes/immunology , Female , Glomerulonephritis/complications , Glomerulonephritis/immunology , Humans , Leukemia, Lymphocytic, Chronic, B-Cell/complicationsABSTRACT
Emergence of multidrug-resistant bacteria is important in solid organ transplant recipients, because it can jeopardize patient and graft survival. Methicillin-resistant Staphylococcus aureus (MRSA) infections are not rare in kidney transplant recipients. On the other hand, infections related to community-associated MRSA (CA-MRSA) strains are seldom reported in the literature. Herein, we report the first patient, to our knowledge, with CA-MRSA renal graft abscess who was successfully treated with drainage and parenteral antibiotics.
Subject(s)
Abscess/microbiology , Community-Acquired Infections/microbiology , Kidney Transplantation/adverse effects , Methicillin-Resistant Staphylococcus aureus/isolation & purification , Staphylococcal Infections/microbiology , Anti-Bacterial Agents/therapeutic use , Female , Humans , Immunocompromised Host , Methicillin Resistance , Middle AgedABSTRACT
Dimethyl thiourea (DMTU), a known hydroxyl radical scavenger, was tested for its ability to improve survival in acute island skin flaps. Rats receiving 500 mg/kg DMTU 1 hour after flap elevation showed a 23.5% improved survival over saline controls. The role of the hydroxyl radical in ischemia/reperfusion injury, and its proposed mechanism, is discussed.
Subject(s)
Graft Survival/drug effects , Hydroxides/metabolism , Surgical Flaps , Thiourea/analogs & derivatives , Animals , Hydroxyl Radical , Male , Microcirculation/drug effects , Rats , Rats, Inbred Strains , Skin/blood supply , Skin/metabolism , Thiourea/pharmacologyABSTRACT
Vitamins A, C, and E act as antioxidants and as free radical scavengers in biological systems. Glutathione is involved in several reactions in vitamin metabolism and also plays an important role in cell membrane protection against lipid peroxidation by free radicals. We sought to use these natural defense mechanisms against oxygen free radicals formed during reperfusion of ischemic skin flaps. An acute axial random skin flap model was utilized in the rat. Vitamins or glutathione were administered by oral gastric tube or intravenously in the perioperative period, and survival of the flap was measured at 1 week. Glutathione, beta-carotene, ascorbic acid and alpha-D-tocopherol showed mean flap survival of 84% to 89%, each of which was significantly improved over saline controls (67% p less than .0005). The mechanisms and biochemistry of these vitamins, and their interactions with other vitamins and with glutathione, are discussed, along with clinical implications of free radical scavenging and skin flap survival.
